Key Points Deletion of αv integrins from B cells accelerates TLR-driven autoimmunity. αv-knockout B cells have increased pathogenic TLR signaling. αv regulates cytokine production and differentiation of IgG2c plasma cells. Systemic lupus erythematosus (SLE) is defined by loss of B cell tolerance, resulting in production of autoantibodies against nucleic acids and other cellular Ags. Aberrant activation of TLRs by self-derived RNA and DNA is strongly associated with SLE in patients and in mouse models, but the mechanism by which TLR signaling to self-ligands is regulated remains poorly understood. In this study, we show that αv integrin plays a critical role in regulating B cell TLR signaling to self-antigens in mice. We show that deletion of αv from B cells accelerates autoantibody production and autoimmune kidney disease in the Tlr7.1 transgenic mouse model of SLE. Increased autoimmunity was associated with specific expansion of transitional B cells, extrafollicular IgG2c-producing plasma cells, and activation of CD4 and CD8 T cells. Our data show that αv-mediated regulation of TLR signaling in B cells is critical for preventing autoimmunity and indicate that loss of αv promotes escape from tolerance. Thus, we identify a new regulatory pathway in autoimmunity and elucidate upstream signals that adjust B cell activation to prevent development of autoimmunity in a mouse model.

中文翻译：

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B 细胞 αv 整合素调节 TLR 驱动的自身免疫

关键点从 B 细胞中删除 αv 整合素可加速 TLR 驱动的自身免疫。αv 基因敲除 B 细胞增加了致病性 TLR 信号。αv 调节 IgG2c 浆细胞的细胞因子产生和分化。系统性红斑狼疮 (SLE) 的定义是 B 细胞耐受性丧失，导致产生针对核酸和其他细胞抗原的自身抗体。在患者和小鼠模型中，自体衍生的 RNA 和 DNA 对 TLR 的异常激活与 SLE 密切相关，但对 TLR 信号传导至自身配体的机制仍知之甚少。在这项研究中，我们表明 αv 整联蛋白在调节 B 细胞 TLR 信号到小鼠自身抗原方面发挥着关键作用。我们表明从 B 细胞中删除 αv 会加速 Tlr7 中的自身抗体产生和自身免疫性肾病。1 SLE 转基因小鼠模型。自身免疫性增强与过渡性 B 细胞、滤泡外产生 IgG2c 的浆细胞的特异性扩增以及 CD4 和 CD8 T 细胞的激活有关。我们的数据表明，αv 介导的 B 细胞 TLR 信号调节对于预防自身免疫至关重要，并表明 αv 的缺失促进了耐受性的逃避。因此，我们确定了一种新的自身免疫调节途径，并阐明了调节 B 细胞活化以防止小鼠模型中自身免疫发展的上游信号。我们的数据表明，αv 介导的 B 细胞 TLR 信号调节对于预防自身免疫至关重要，并表明 αv 的缺失促进了耐受性的逃避。因此，我们确定了一种新的自身免疫调节途径，并阐明了调节 B 细胞活化以防止小鼠模型中自身免疫发展的上游信号。我们的数据表明，αv 介导的 B 细胞 TLR 信号调节对于预防自身免疫至关重要，并表明 αv 的缺失促进了耐受性的逃避。因此，我们确定了一种新的自身免疫调节途径，并阐明了调节 B 细胞活化以防止小鼠模型中自身免疫发展的上游信号。